{"title":"GDF15通过抑制cGAS-STING通路的激活来减缓帕金森病的进展。","authors":"Jianli Wang, Ting Geng, Xiaomei Yao, Yiming Liu","doi":"10.1007/s11010-025-05265-4","DOIUrl":null,"url":null,"abstract":"<p><p>Growth differentiation Factor 15 (GDF15) plays an important role in the innate immune response. However, whether GDF15 could regulate Parkinson's disease (PD) remains unknown. In this study, we explored the function and underlying molecular mechanisms of GDF15 in PD. The protein and mRNA expressions were examined applying immunofluorescence staining, Western blot and qRT-PCR. Ferrous iron content was also assessed using an iron assay kit. The effect of GDF15 knockdown on mitochondrial membrane potential, ROS level, intracellular Fe<sup>2+</sup> level and mitochondrial permeability transition pore opening in PD cell model was evaluated utilizing JC-1 staining, DCFH-DA fluorescent probe, ferro orange staining and calcein AM + Co<sup>2+</sup> quencher staining. GDF15 was upregulated in the substantia nigra and striatum of PD mice and MPP<sup>+</sup>-caused SH-SY5Y cells. GDF15 knockdown aggravated parkinsonian symptoms in PD mice. Moreover, GDF15 knockdown aggravated dopamine neuronal damage, and promoted ferroptosis and inflammation in PD in vivo and in vitro. Besides, GDF15 knockdown could activate cGAS-STING pathway in vivo and in vitro PD model. We also found that the treatment of RU.521 could reverse the effect of GDF15 knockdown on dopamine neuronal damage, inflammation and ferroptosis in MPP<sup>+</sup>-induced SH-SY5Y cells. Similarly, the treatment of SR-717 could reverse the effect of GDF15 overexpression on dopamine neuronal damage, inflammation and ferroptosis in MPP<sup>+</sup>-induced SH-SY5Y cells. The results of this study demonstrated that GDF15 could attenuate dopamine neuronal damage, and inhibit ferroptosis and inflammation in PD via suppressing cGAS-STING pathway activation.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":"4449-4466"},"PeriodicalIF":3.5000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"GDF15 attenuates Parkinson's disease progression via suppressing the activation of cGAS-STING pathway.\",\"authors\":\"Jianli Wang, Ting Geng, Xiaomei Yao, Yiming Liu\",\"doi\":\"10.1007/s11010-025-05265-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Growth differentiation Factor 15 (GDF15) plays an important role in the innate immune response. However, whether GDF15 could regulate Parkinson's disease (PD) remains unknown. In this study, we explored the function and underlying molecular mechanisms of GDF15 in PD. The protein and mRNA expressions were examined applying immunofluorescence staining, Western blot and qRT-PCR. Ferrous iron content was also assessed using an iron assay kit. The effect of GDF15 knockdown on mitochondrial membrane potential, ROS level, intracellular Fe<sup>2+</sup> level and mitochondrial permeability transition pore opening in PD cell model was evaluated utilizing JC-1 staining, DCFH-DA fluorescent probe, ferro orange staining and calcein AM + Co<sup>2+</sup> quencher staining. GDF15 was upregulated in the substantia nigra and striatum of PD mice and MPP<sup>+</sup>-caused SH-SY5Y cells. GDF15 knockdown aggravated parkinsonian symptoms in PD mice. Moreover, GDF15 knockdown aggravated dopamine neuronal damage, and promoted ferroptosis and inflammation in PD in vivo and in vitro. Besides, GDF15 knockdown could activate cGAS-STING pathway in vivo and in vitro PD model. We also found that the treatment of RU.521 could reverse the effect of GDF15 knockdown on dopamine neuronal damage, inflammation and ferroptosis in MPP<sup>+</sup>-induced SH-SY5Y cells. Similarly, the treatment of SR-717 could reverse the effect of GDF15 overexpression on dopamine neuronal damage, inflammation and ferroptosis in MPP<sup>+</sup>-induced SH-SY5Y cells. The results of this study demonstrated that GDF15 could attenuate dopamine neuronal damage, and inhibit ferroptosis and inflammation in PD via suppressing cGAS-STING pathway activation.</p>\",\"PeriodicalId\":18724,\"journal\":{\"name\":\"Molecular and Cellular Biochemistry\",\"volume\":\" \",\"pages\":\"4449-4466\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2025-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular and Cellular Biochemistry\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1007/s11010-025-05265-4\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/4/3 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular and Cellular Biochemistry","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1007/s11010-025-05265-4","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/4/3 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
GDF15 attenuates Parkinson's disease progression via suppressing the activation of cGAS-STING pathway.
Growth differentiation Factor 15 (GDF15) plays an important role in the innate immune response. However, whether GDF15 could regulate Parkinson's disease (PD) remains unknown. In this study, we explored the function and underlying molecular mechanisms of GDF15 in PD. The protein and mRNA expressions were examined applying immunofluorescence staining, Western blot and qRT-PCR. Ferrous iron content was also assessed using an iron assay kit. The effect of GDF15 knockdown on mitochondrial membrane potential, ROS level, intracellular Fe2+ level and mitochondrial permeability transition pore opening in PD cell model was evaluated utilizing JC-1 staining, DCFH-DA fluorescent probe, ferro orange staining and calcein AM + Co2+ quencher staining. GDF15 was upregulated in the substantia nigra and striatum of PD mice and MPP+-caused SH-SY5Y cells. GDF15 knockdown aggravated parkinsonian symptoms in PD mice. Moreover, GDF15 knockdown aggravated dopamine neuronal damage, and promoted ferroptosis and inflammation in PD in vivo and in vitro. Besides, GDF15 knockdown could activate cGAS-STING pathway in vivo and in vitro PD model. We also found that the treatment of RU.521 could reverse the effect of GDF15 knockdown on dopamine neuronal damage, inflammation and ferroptosis in MPP+-induced SH-SY5Y cells. Similarly, the treatment of SR-717 could reverse the effect of GDF15 overexpression on dopamine neuronal damage, inflammation and ferroptosis in MPP+-induced SH-SY5Y cells. The results of this study demonstrated that GDF15 could attenuate dopamine neuronal damage, and inhibit ferroptosis and inflammation in PD via suppressing cGAS-STING pathway activation.
期刊介绍:
Molecular and Cellular Biochemistry: An International Journal for Chemical Biology in Health and Disease publishes original research papers and short communications in all areas of the biochemical sciences, emphasizing novel findings relevant to the biochemical basis of cellular function and disease processes, as well as the mechanics of action of hormones and chemical agents. Coverage includes membrane transport, receptor mechanism, immune response, secretory processes, and cytoskeletal function, as well as biochemical structure-function relationships in the cell.
In addition to the reports of original research, the journal publishes state of the art reviews. Specific subjects covered by Molecular and Cellular Biochemistry include cellular metabolism, cellular pathophysiology, enzymology, ion transport, lipid biochemistry, membrane biochemistry, molecular biology, nuclear structure and function, and protein chemistry.